Ubiquitin–proteasome system in the different stages of dominantly inherited Alzheimer's disease

Liu, Haiyan; Bui, Quoc; Hassenstab, Jason; Gordon, Brian A.; Benzinger, Tammie L. S.; Timsina, Jigyasha; Sung, Yun Ju; Karch, Celeste; Renton, Alan E.; Daniels, Alisha; Morris, John C.; Xiong, Chengjie; Ibanez, Laura; Perrin, Richard J.; Llibre‐Guerra, Jorge J.; Day, Gregory S.; Supnet‐Bell, Charlene; Xu, Xiong; Berman, Sarah B.; Chhatwal, Jasmeer P.; Ikeuchi, Takeshi; Kasuga, Kensaku; Niimi, Yoshiki; Huey, Edward D.; Schofield, Peter R.; Brooks, William S.; Ryan, Natalie S.; Jucker, Mathias; Laske, Christoph; Levin, Johannes ; Vöglein, Jonathan ; Roh, Jee Hoon; Lopera, Francisco; Bateman, Randall J.; Cruchaga, Carlos und McDade, Eric M. (2025): Ubiquitin–proteasome system in the different stages of dominantly inherited Alzheimer's disease. In: Alzheimer's & Dementia, Bd. 21, Nr. 5, e70243

Abstract

INTRODUCTION

This study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.

METHOD

The SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.

RESULTS

Subtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS-activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late-stage tau biomarkers, microglia, and axonal degeneration.

DISCUSSION

The rise in UPS proteins alongside tau-related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1552-5260
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198